KR101199196B1 - Manufacturing method for spheric granule of pancreatin - Google Patents

Abstract

The present invention includes a process of spraying a spherical pellet in a fluidized bed granulator while dissolving or dispersing a pancreatin solution or dispersion in water, in the process of dissolving or dispersing pancreatin in water Method of preparing a spherical pancreatin granules, characterized in that divided into the amount that can be sprayed within 20 to 90 minutes from the preparation, and spraying is completed within that time and using the granules prepared in such a manner It relates to a method for preparing enteric pancreatin granules.

The present invention provides a method for minimizing the enzymatic inactivation of pancreatin by solvent and heat, and safely preparing spherical pancreatin granules with uniform particle size in a minimal process. In addition, there is provided a method for producing enteric pancreatin granules having a uniform enteric coating film using the granules prepared by such a method.

Pancreatin, Enteric, Granule, Spherical

Description

Manufacturing method for spheric granules of pancreatin

1 is a photograph taken with a microscope of the spherical pancreatin granules prepared according to the present invention.

Figure 2 is a microscope photograph of the spherical enteric pancreatin granules prepared according to the present invention.

Figure 3 is a microscope photograph of the cross section of the spherical enteric pancreatin granules prepared according to the present invention.

Figure 4a and 4b is a schematic diagram of the manufacturing process of the pancreatin granules according to the prior art, 4c is a schematic diagram of the manufacturing process of the pancreatin granules according to the present invention.

The present invention relates to a method for producing spherical pancreatin granules and a method for preparing enteric pancreatin granules by coating the granules prepared by such a method.

Enzymes secreted from the pancreas of animals are mainly composed of starch digestive enzymes, protein digestive enzymes, and fat digestive enzymes. Pancreatin is made from pancreatic enzymes derived from animals and consists mainly of starch digestive enzymes, protein digestive enzymes, and fat digestive enzymes. Enzymes produced by the pancreas are secreted into the duodenum. The pH of the duodenum is close to neutral or slightly alkaline, and under these pH conditions, the enzyme becomes active and digests food by the enzyme. However, when administered orally, pancreatic enzymes are inactivated by intragastric pH conditions. Therefore, orally administered enzymes must be protected from inactivation by gastric acid and reach the duodenum, and when the administered enzymes reach the duodenum, the enzymes must be released from their protective bodies and mixed well with the food.

In addition to pancreatic enzymes, preparations containing enzymes or drugs that act in the general intestine should not (1) be exposed to a pH level below a certain level to degrade the drug, and (2) no side effects due to the action of the drug. , (3) The drug should not be dissolved in the intestine and the concentration of the drug should not be diluted.

In general, enteric coating of pharmaceutical preparations is used for the purpose of protecting the active ingredient from the acid of gastric juice. In the case of general enteric coating pharmaceuticals, the purpose has been achieved by coating the surface of the tablet. Recently, however, it has been reported that enteric coated granules show no individual difference in gastric residence time and absorption and are hardly affected by food compared to enteric coated tablets from a biopharmaceutical point of view.

The most commonly used enteric coating to impart enteric drugs, the thickness and uniformity of the enteric coating membrane coated on the particles or tablets is a very important factor. When the thickness of the enteric coating membrane is not uniform, not only does it interfere with the protection of the active ingredient against acid of gastric juice, but also reacts sensitively to the environmental difference in vivo, resulting in many deviations not only between individuals but also within individuals.

In the case of powder coating, since the surface area is very large and the particle size and shape are coated on the powder, it is impossible to equalize the enteric coating film thickness between the powders. In order to overcome this, enteric coating is generally performed after preparing granules of a predetermined size or more. However, due to the limitations of the method of producing granules, it is difficult to produce particles of uniform size, making uniform enteric coating difficult. Therefore, in order to manufacture spherical enteric granules having a uniform enteric coating membrane, it is a good idea to prepare spherical granules having a uniform particle size.

Vacuum drying and extruder granulators by extrusion molding have generally been used in the granulation process of pancreatin. These methods produce granules by processes such as coalescence, granulation, sizing, drying and sieving. However, this method is very complicated in the process itself. In addition, most of the granules produced by this method are not completely spherical and have a wide granule size distribution problem, making it impossible to produce enteric pancreatin granules having a uniform enteric coating.

The manufacturing method using centrifugal fluidized-bed coating granulator (hereinafter referred to as CF granulator) was introduced to overcome problems such as uneven size distribution of granules and incomplete production of spherical granules. It is a method for producing spherical granules using. This method is capable of producing spherical granules, and the size distribution has been improved over the above manufacturing method, but there is a high risk of breakage and destruction of the spherical granules at the beginning of the manufacturing process, and the surface of the granules made is somewhat rough and uniform The disadvantage is that the coating is difficult.

Enzymes, which are the major components of pancreatin, are composed of proteins, which lose their activity when the conformation is denatured by heat and solvent.

In particular, pancreatin is known to have very low enzymatic activity because pancreatin granules prepared using water as a solvent are very unstable in water. In fact, when the pancreatin granules are prepared using water as a solvent according to a conventional granulation process, in the case of fat digestase, which is a major component of pancreatin, the activity of the enzyme is lost to about 50%. Therefore, despite the advantages of safety and simplicity, it has been recognized that the production of pancreatin granules using water as a solvent has no economic value.

Therefore, the organic solvent was mainly used in the manufacturing process of the conventional pancreatin granules. This is because the organic solvent has a low boiling point and is easy to remove from the pancreatin granules, and the loss of enzymatic activity by the solvent is not large in the manufacturing process of the granules, which usually take 3 to 4 hours. Ethanol, acetone and the like are frequently used as the organic solvent. However, the use of such an organic solvent has a problem that it is difficult to remove 100% in the actual process despite the possibility of causing toxicity to the human body.

The present inventors have diligently studied to solve the above problems, and as a result, pancreatin is unstable in water, but unlike the conventional manufacturing method, when granules are prepared under constant conditions, the decrease in enzyme activity is minimized even when water is used as a solvent. The present invention was completed by discovering a groundbreaking fact that pancreatin granules can be produced by the process of.

It is therefore an object of the present invention to provide a method for minimizing the enzyme inactivation of pancreatin by solvent and heat, and safely preparing spherical pancreatin granules with uniform particle size in a minimal process. It is also an object of the present invention to provide a method for producing enteric pancreatin granules having a uniform enteric coating film using the granules prepared by such a method.

The present invention includes a process of spraying a spherical pellet in a fluidized bed granulator while dissolving or dispersing a pancreatin solution or dispersion in water, in the process of dissolving or dispersing pancreatin in water It is prepared by dividing the pancreatin solution or dispersion by the amount that can be sprayed within 20 to 90 minutes from the spherical pancreatin granules, characterized in that the spraying is completed within that time.

The specific manufacturing method of the spherical pancreatin granule of this invention is as follows.

Spherical pancreatin granules can be manufactured by the process of spraying the pellet which melt | dissolved or disperse | distributed pancreatine in water, and sprinkling a spherical pellet in a fluidized bed granulator. As the water used, purified water is preferable.

Inactivation of the enzyme by the water used as a solvent in the above production method is prepared by dividing the pancreatin solution or dispersion into an amount that can be sprayed within 20 to 90 minutes from the point of dissolving or dispersing pancreatin in water, and This can be minimized by completing the injection in time. More preferably, the pancreatin solution or dispersion is prepared by dividing the pancreatin solution into the amount that can be sprayed within 40 to 70 minutes from the point of dissolving or dispersing the pancreatin in a solvent, and the spraying is completed within that time.

If the time from preparation of pancreatin solution or dispersion to completion of spraying exceeds 90 minutes, the activity of the enzyme contained in pancreatin is greatly reduced (in the case of aliphatic enzyme, the loss of enzyme activity exceeds 20%). It is difficult to produce and production of pancreatin granules on an industrial scale is difficult because of less than 20 minutes of working time.

The pellets used above may be used as long as they are pharmaceutically acceptable spherical particles, and preferably, the particle diameter is 200 to 1,000 µm, but is not limited thereto. Spherical pellets may be made of celluloses, starches or sugars alone or in combination of two or more thereof, and may be all made of pharmaceutically acceptable excipients.

In order to prevent adhesion or adhesion between the fluidized bed granulator and the particles and adhesion or adhesion between the particles during coating, talc, magnesium stearate, and light silicic anhydride, alone or in combination, are added to a solution in which pancreatin is dissolved or dispersed in a solvent. It can be used, but is not limited to this material.

The present invention also provides a spherical enteric plate comprising the step of spraying the spherical pancreatin granules prepared above in a fluidized bed granulator while dissolving or dispersing the enteric coating polymer into the granules. It relates to the preparation of creatine granules.

The preparation method of the spherical enteric pancreatin granules is specifically as follows.

The spherical enteric pancreatin granules can be prepared by the step of spraying the spherical pancreatin granules prepared above in a fluidized bed granulator while dissolving or dispersing the enteric coating polymer into the granules.

In the above enteric coating polymer may be used alone or in combination of a water-soluble polymer or a water-insoluble polymer that does not dissolve at pH 3.0 or less. Eudragit L30 D-55 is the most preferred enteric coating polymer, but is not limited thereto, and other enteric coating polymers known in the art, such as polyvinyl acetate phthalate, acrylic acid polymers, acrylic acid aerials Pharmaceutically acceptable enteric coating polymers such as coalescing, cellulose acetate phthalate can be used.

In the above enteric coating solution or dispersion is preferably prepared by dissolving or dispersing the enteric coating polymer in water. Water used as the solvent is preferably purified water.

It is preferable that the solution which melt | dissolved or dispersed the enteric coating polymer in the above contains a plasticizer. It is preferable to use triethyl citrate as the plasticizer, but the present invention is not limited thereto, and any other plasticizer such as pharmaceutically acceptable plasticizers such as triacetin and polyethylene glycol can be used.

In the above enteric coating may be sprayed by adding a coloring agent with the spherical granules, or added to the enteric coating solution or dispersion in order to increase the marketability. In this case, as the colorant used, talc, titanium oxide, iron oxide, tar pigment, or lakes thereof may be used, and the present invention is not limited thereto, and any pharmaceutically acceptable and coloring material may be used.

In order to prevent adhesion or adhesion between the fluidized bed granulator and the particles and adhesion or adhesion between the particles, the talc, titanium oxide, and the like may be added to the coating solution alone or in combination. However, the present invention is not limited thereto. .

According to the present invention, it is safe to use spherical pancreatin granules having a uniform particle size distribution which is safe by using water as a solvent for dissolving or dispersing pancreatin and employing a fluidized bed granulator, and minimizing the enzyme inactivation of pancreatin. In addition, enteric pancreatin granules having a uniform enteric coating film can be produced easily.

Spherical pancreatin granules or spherical enteric pancreatin granules obtained by the production method of the present invention can be used in solid preparations such as granules, capsules and tablets.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. However, the present invention is not limited by these examples and experimental examples.

EXAMPLE 1 Preparation of Spherical Pancreatin Granules

Spherical pancreatin granules were sprayed by dispersing 800 g of pancreatin in 3.2 L of purified water while flowing 200 g of pellets made of white sugar and corn starch in a fluidized bed granulator with a particle size ranging from 600 µm to 710 µm (Nos. 25 to 30). Was prepared. At this time, the injection conditions were adjusted so that the product temperature inside the fluidized bed is maintained at 40 ℃ or less. The pancreatin dispersion was prepared by dividing the pancreatin into an amount that can be sprayed within 60 minutes from the time of dispersing the pancreatin in purified water, and spraying was completed within that time.

EXAMPLE 2 Preparation of Spherical Pancreatin Granules

While the particle size ranges from 355 to 425 μm (No. 40 to 45), 200g of pellets made of white sugar and corn starch are flowed in a fluidized bed granulator while 800g of pancreatin dispersed in 3.2L of purified water is sprayed to form spherical pancreatin granules. Prepared. At this time, the injection conditions were adjusted so that the product temperature inside the fluidized bed is maintained at 40 ℃ or less. The pancreatin dispersion was prepared by dividing the pancreatin into an amount that can be sprayed within 60 minutes from the time of dispersing the pancreatin in purified water, and spraying was completed within that time.

Example 3 Preparation of Spherical Pancreatin Granules

Spherical pancreatin granules were sprayed by spraying a solution of 800 g of pancreatin dispersed in 3.2 liters of purified water while flowing 200 g of pellets made of white sugar and corn starch in a fluidized bed granulator with a particle size of 212 to 250 µm (No. 60 to 70). Prepared. At this time, the injection temperature was adjusted to maintain the product temperature in the fluidized bed below 40 ℃. The pancreatin dispersion was prepared by dividing the pancreatin into an amount that can be sprayed within 60 minutes from the time of dispersing the pancreatin in purified water, and spraying was completed within that time.

Example 4 Preparation of Spherical Pancreatin Granules

While the particle size ranges from 355 to 425 μm (No. 40 to 45), 200g of pellets made of white sugar and corn starch are flowed into a fluidized bed granulator while 800g of creatine and 15g of hydroxypropylcellulose are dispersed in 3.2L of purified water. Spherical pancreatin granules were prepared. At this time, the injection conditions were adjusted so that the product temperature inside the fluidized bed is maintained at 40 ℃ or less. The pancreatin dispersion was prepared by dividing the pancreatin into an amount that can be sprayed within 60 minutes from the time of dispersing the pancreatin in purified water, and spraying was completed within that time.

Example 5 Preparation of Spherical Pancreatin Granules

Spherical pancreatin granules were prepared in the same manner as in Example 1 except that the pancreatin dispersion was prepared by dividing the pancreatin dispersion into an amount that can be sprayed within 90 minutes from the time when the pancreatin was dispersed in purified water. Prepared.

Example 6. Preparation of Spherical Enteric Pancreatin Granules

While spherical pancreatin granules prepared in Example 1 were flowed in a fluidized bed granulator, 200 g of Eudragit L30 D-55 (solid content), 22 g of triethyl citrate, and 65.6 g of talc were dispersed in 1.3 L of purified water. Enteric pancreatin granules were prepared by spraying.

Example 7. Preparation of Spherical Enteric Pancreatin Granules

The spherical pancreatin granules prepared in Example 2 were dispersed in a fluidized bed granulator with 300 g of Eudragit L30 D-55 (amount of solids), 33 g of triethyl citrate and 98.4 g of talc in 1.95 L of purified water. Enteric pancreatin granules were prepared by spraying.

Example 8. Preparation of Spherical Enteric Pancreatin Granules

While the spherical pancreatin granules prepared in Example 3 were flowed in a fluidized bed granulator, 500 g of Eudragit L30 D-55 (solid amount), 55 g of triethyl citrate, and 164 g of talc were dispersed in 3.25 L of purified water. Enteric pancreatin granules were prepared by spraying.

Example 9. Preparation of Spherical Enteric Pancreatin Granules (Coloring)

Spherical pancreatin granules prepared in Example 1 were flowed in a fluidized bed granulator and 200 g of Eudragit L30 D-55 (solid amount), 22 g of triethyl citrate, 45.6 g of titanium oxide, and talc 65.6 in 1.3 L of purified water. Enteric pancreatin granules were prepared by spraying a dispersion of g. The enteric granules produced were white.

Comparative Example 1. Preparation of Spherical Pancreatin Granules

Spherical pancreatin granules were prepared in the same manner as in Example 1, except that the pancreatin dispersion was prepared by dividing the pancreatin dispersion into an amount that can be sprayed within 120 minutes from the time when the pancreatin was dispersed in purified water. Prepared.

Comparative Example 2. Preparation of Spherical Pancreatin Granules

Spherical pancreatin granules were prepared in the same manner as in Example 1 except that the pancreatin dispersion was prepared by dividing the pancreatin dispersion into an amount that can be sprayed within 150 minutes from the time when the pancreatin was dispersed in purified water. Prepared.

Comparative Example 3. Preparation of Spherical Pancreatin Granules

Spherical pancreatin granules were prepared in the same manner as in Example 1, except that the pancreatin dispersion was prepared by dividing the pancreatin dispersion into an amount that can be sprayed within 180 minutes from the time when the pancreatin was dispersed in purified water. Prepared.

Comparative Example 4. Preparation of Spherical Pancreatin Granules

Spherical pancreatin granules were prepared in the same manner as in Example 1 except that the pancreatin dispersion was prepared by dividing the pancreatin dispersion into an amount that can be sprayed within 240 minutes from the time when the pancreatin was dispersed in purified water. Prepared.

Experimental Example 1. Confirmation of Particle Size Distribution

The particle size distribution of each spherical pancreatin granules prepared in Examples 1 to 4 and each spherical enteric pancreatin granules prepared in 6 to 9 was evaluated using a sieve shaker.

Particle size distribution evaluation result Size (㎛) Example 1 Example 2 Example 3 Example 4 Example 6 Example 7 Example 8 Example 9 1,700 or more - - _ - 1.0 - - - 1,400-1,700 56.0 - _ - 98.1 - - - 1,180-1,400 43.6 - _ - 0.9 - - - 1,000 to 1,180 0.4 - _ - - - - - 850 to 1,000 - - _ 0.1 - 12.1 - 10.4 710 to 850 - 30.7 _ 33.8 - 80.5 - 81.2 600 to 710 - 67.8 _ 65.7 - 7.4 - 8.4 500-600 - 1.5 _ 0.4 - - 1.5 - 425 to 500 - 0.1 24.6 _ - - 97.4 - 355-425 - - 72.5 - - - 1.1 - 300 to 355 - - 2.9 - - - - - 300 or less - - - - - - - -

Experimental Example 2. Acid Resistance Test

When the acid resistance test of the enteric coating granules prepared in Examples 6 to 9 was performed at 900 rpm for 2 hours at 37 ° C. for 2 hours using 900 mL of KP, there was no damage to the coating film in all formulations. It was confirmed that the dissolution of the drug hardly occurs even in the acid resistance test results of the dissolution rate test of the.

Acid resistance test result (dissolution rate%) Item Example 6 Example 7 Example 8 Example 9 Lipase Dissolution Rate (%) 4.2 3.5 3.3 3.6

Experimental Example 3. Enzyme activation test

Enzyme activation was measured by USP method for the spherical pancreatin granules prepared in Examples 1 and 5 compared to the spherical pancreatin granules prepared in Examples 1 to 4, thereby changing the enzyme activation during the manufacturing process. (Deactivation degree) was evaluated.

Changes in enzyme activation during the manufacturing process Spray quantity of pancreatin solution or dispersion used Recovery rate Starch digestive enzyme Aliphatic enzymes Protease Example 1 60min 95.3% 95.3% 99.8% Example 2 90min 97.9% 81.5% 91.0% Comparative Example 1 120 min 95.6% 75.0% 89.8% Comparative Example 2 150min 86.5% 69.2% 85.4% Comparative Example 3 180 min 84.4% 54.9% 83.6% Comparative Example 4 240min 80.5% 42.5% 78.6%

As shown in Table 3, Examples 1 and 2 prepared by dividing the pancreatin dispersion into an amount that can be sprayed within 90 minutes from the time when dispersing the pancreatin in purified water, and finished the injection within that time In the case of pancreatin granules, it was confirmed that the change in enzyme activation during the manufacturing process was not large. However, Comparative Examples prepared by dividing the pancreatin dispersion into a portion that can be sprayed within 120 minutes, 150 minutes, 180 minutes, and 240 minutes, respectively, from the time when the pancreatin was dispersed in purified water, and the injection was completed within that time. In the case of the pancreatin granules of 1 to 4, it was confirmed that the enzyme activation during the manufacturing process was greatly reduced (particularly, the aliphatic enzyme), which is unsuitable for industrial production.

The present invention provides a method for minimizing the enzymatic inactivation of pancreatin by solvent and heat, and safely preparing spherical pancreatin granules with uniform particle size in a minimal process. Also provided is a method for producing enteric pancreatin granules having a uniform enteric coating film using the granules prepared in such a manner.

Claims (16)

(1) spherical pellets having a diameter of 200 to 1,000 µm and made of one or more components selected from the group consisting of celluloses, starches and sugars, while flowing in a fluidized bed granulator, Spherical pancreatin granules are prepared by dissolving or dispersing a pancreatin solution or dispersion dissolved in water into the pellets, wherein the pancreatin granules can be sprayed within 20 to 90 minutes from the point of dissolving or dispersing pancreatin in water. Prepare a portion of the pancreatin solution or dispersion in a predetermined amount, and complete the spraying within that time; And (2) spherical enteric pancreatin, comprising the step of spraying the prepared spherical pancreatin granules in the fluidized bed granulator while dissolving or dispersing the enteric coating polymer or dispersion into the granules. Method for producing granules. The method for producing spherical enteric pancreatin granules according to claim 1, wherein water used as a solvent in the step of producing the spherical pancreatin granules of (1) is purified water. The process according to claim 1, wherein the pancreatin solution or dispersion is divided by the amount that can be sprayed within 40 to 70 minutes from the point of dissolving or dispersing the pancreatin in water in the process of producing the spherical pancreatin granule of (1). A method for producing spherical enteric pancreatin granules, which is prepared, and the spraying is completed within the time. delete delete The method for producing spherical enteric pancreatin granules according to claim 1, wherein in the step of producing the spherical pancreatin granules of (1), a binder is added and sprayed to the pancreatin solution or dispersion. The method for producing spherical enteric pancreatin granules according to claim 6, wherein the binder is hydroxypropyl cellulose, hydroxypropyl methyl cellulose or carboxymethyl cellulose. The talc, magnesium stearate and hard silicic anhydride according to claim 1, in order to prevent adhesion or adhesion between the fluidized bed granulator and particles and adhesion or adhesion between particles in the process of producing the spherical pancreatin granules of (1). A method for producing spherical enteric pancreatin granules, characterized in that it is used by adding at least one component selected from the group consisting of a pancreatin solution or dispersion. delete The method for producing spherical enteric pancreatin granules according to claim 1, wherein the enteric coating polymer is used alone or in combination with a water-soluble polymer or a water-insoluble polymer which does not dissolve at pH 3.0 or lower. The method for producing spherical enteric pancreatin granules according to claim 1, wherein the enteric coating solution or dispersion is prepared by dissolving or dispersing the enteric coating polymer in purified water. The method for preparing spherical enteric pancreatin granules according to claim 1, wherein the enteric coating solution or dispersion contains a plasticizer. 13. The process for producing spherical enteric pancreatin granules according to claim 12, wherein the plasticizer is triethylcitrate, triacetin or polyethylene glycol. The method for preparing spherical enteric pancreatin granules according to claim 1, wherein the colorant is used together with the spherical granules or added to an enteric coating solution or dispersion. 15. The method for producing spherical enteric pancreatin granules according to claim 14, wherein the colorant is talc, titanium oxide, iron oxide, tar tar, or lakes thereof. The enteric coating solution according to claim 1, wherein at least one component selected from the group consisting of talc and titanium oxide is prevented in order to prevent adhesion or adhesion between the fluidized bed granulator and the particles and adhesion or adhesion between the particles during the coating in the step (2). Or spherical enteric pancreatin granules, characterized in that used in addition to the dispersion.

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